Investigating Ultrastructural Collagen Changes in Osteogenesis Imperfecta

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DESCRIPTION (provided by applicant): The lack of understanding of how altered collagen structure in Osteogenesis Imperfecta (Ol) translates to insufficiencies in tissue integrity is a critical impediment to the implementation of treatment protocols designed to return bone properties to normal levels. The long-term goal is to understand how alterations in the bone ultrastructure in Ol influence higher level properties. The overall objective of this proposal is to relate [morphological changes] in Type I collagen fibrils from connective tissues of Ol mice [to fibril mechanical integrity and] the altered ability of proteins to bind to this collagen as measures of functional competence. The central hypothesis is that alterations in the [width, axial spacing and packing] of Ol Type I collagen fibrils will result in inappropriate organic matrix organization, [decreased fibril modulus] and [improper protein binding to diseased fibril] surfaces. The rationale for the proposed research is that once mechanical differences in Ol [tissues] can be linked to explicit changes in Type I collagen, appropriate treatment options can be developed to specifically target altered collagen functions. Therefore, this research is relevant to the NIH's mission to apply fundamental knowledge about the nature of living systems to extending healthy human life and reducing the burdens of illness and disability. Based on strong preliminary data and a solid literature base, the central hypothesis will be tested by pursuing two specific aims: 1) Identify morphological and organizational consequences of Ol in Type I collagen; and 2) Establish changes [in mechanical integrity and] in the ability of proteins to bind to Type I collagen in Ol as measures of functional competence. Atomic force microscopy coupled with dendritic polymers as model proteins will be used to probe the collagen of wild type, [Brtl/+] and [Brtl/Brtl] mice representing a [range] of Ol severity. Under the first aim, Type I collagen will be imaged in a variety of biological settings to determine how collagen physically [changes with mutation severity]. Under the second aim, physical differences in collagen will be correlated [with fibril modulus and] with alterations in the ability of proteins to bind to fibril surfaces as measures of functionality. The approach is innovative because it will begin linking architectural and functional aspects of Type I collagen at the ultrastructural level to higher-level properties in situ. As the United States is part of the current worldwide Bone and Joint Decade initiative, this research has clear relevance to public health. Uncovering the link between bone quality and structural integrity remains a key goal of the bone research community. Therefore, this research is not only applicable to Ol patients, but has broader implications for investigating other diseases related to ultrastructural modifications of bone.